LONDON – Uniqure NV is ditching its world-first gene therapy Glybera and will not renew the European license when it expires on Oct. 25. If that is a sad end to one of the most protracted drug development sagas in history, it undoubtedly sets a bad precedent for expensive one-off therapies coming through the pipeline – for which Uniqure's persistence with the EMA did so much to forge the way.

It also adds to the list of products approved under the advanced therapy medicinal product (ATMP) route that have been commercial flops.

Glybera is the most expensive drug in the world, at €1.1 million (US$1.2 million) for a single treatment.

"This must send a warning message to other companies about the willingness to pay for these products in Europe," said Alastair Kent, director of Genetic Alliance UK, an umbrella group representing 180 rare disease patient organizations.

"It's a shame the company and various national health systems could not find an accommodation to allow a very small number of patients with very big medical needs to benefit from what is clearly an effective therapy," Kent told BioWorld Today.

The move to ax Glybera (alipogene tiparvovec) "is based on economic reasons and that demand is less than expected," said Eva Mulder, Uniqure's head of investor relations. Uptake of the product was not blocked because of its price, but because of high patient inclusion criteria, Mulder told BioWorld Today.

In the 4.5 years since the landmark approval of the treatment for inherited lipoprotein lipase deficiency, only one patient has received the commercial product, which is reimbursed in Germany and Italy. Mulder said there are patients lined up for treatment and that will go ahead as long as reimbursement is agreed before the license expires.

The phase IV post-approval study the EMA required when it granted approval will be terminated.

Uniqure had expected European approval to smooth the path to the U.S. market, but the FDA asked for two further trials. That led the company to drop plans for U.S. commercialization in December 2015.

When the European Commission granted a five-year marketing authorization for Glybera under exceptional circumstances in October 2012, the terms required that the company establish a global registry for the long-term surveillance of patients, conduct a post-approval clinical study, submit for annual regulatory reassessments and implement additional risk management procedures.

Uniqure said those activities require a significant infrastructure that includes bearing the full costs of maintaining commercial manufacturing capabilities, managing development and validation of numerous assays and supporting regulatory interactions and inspections. As a result of withdrawal from the European market, Amsterdam, the Netherlands-based Uniqure expects cost savings of $2 million per annum.

The company announced previously that it would not transfer production of Glybera to the U.S., where it is concentrating commercial-scale manufacturing at its facility in Lexington, Mass., and the savings from scrapping Glybera are in addition to those made by that consolidation.

UNMET NEEDS REMAIN UNMET

After 14 years in development, Glybera won its place in the history books when it crossed the finish line in October 2012, following EMA's fourth review of the file.

In the course of controversial deliberations, EMA committees found themselves at odds, with the Committee for Advanced Therapies and the Scientific Advisory Group recommending approval, while the Committee for Medicinal Products for Human Use (CHMP) was against it.

The European Commission for the first – and only time to date – refused to give its usual rubber stamp when CHMP recommended that Glybera be rejected, telling it to think again. (See BioWorld Today, July 23, 2012.)

Although the €1.1 million cost of Glybera might provoke sharp drawing in of breath, as a one-off treatment whose effects last over years, it is not out of line with enzyme replacement therapies that cost between €150,000 and €450,000 per patient, per year.

Lipoprotein lipase deficiency cannot be treated with enzyme replacement therapy because the naturally occurring enzyme has a very short half-life. The only way to prevent recurrent attacks of pancreatitis caused by undigested fat is to have a completely fat-free diet.

"The pity is that unmet needs remain unmet, when we could meet them," Kent said. "The scrapping of Glybera adds to the pressure to create a reimbursement framework for high-cost, one-off products that allows companies to get a return on investment whilst at the same time avoiding an unsustainable financial on health care systems," he said.

The withdrawal of Glybera casts another shadow over EMA's ATMP regulations. The first product to be approved under the route, Tigenix NV's Chondrocelect, an autologous treatment for damaged knee cartilage, was also a commercial failure.

The EU license for Dendreon Inc.'s Provenge (sipuleucel-T) was withdrawn when the product flopped in the U.S. and the license for MACI (autologous cultured chondrocytes on porcine collagen membrane) was withdrawn when its owner, Aastrom Biosciences Inc., closed the EMA-licensed manufacturing facility in Denmark (its new owner Vericel Corp. won FDA approval for the product in December 2016).

Following consultations in May 2016, the EMA is now looking at how to improve its oversight of ATMPs. A plan with actions to improve the regulatory and scientific environment is promised for 2017. There remains one marketed gene therapy, Glaxosmithkline plc's Strimvelis (GSK 2696273), an ex vivo therapy for ADA-SCID (severe combined immunodeficiency due to adenosine deaminase deficiency). The company reached agreement with the Italian medicines regulator, Agenzia Italiano del Farmaco (AIFA) on Aug. 26, 2016, to pay €594,000 per treatment. The 15 children per year from across Europe who require Strimvelis will all be treated in the Ospedale San Raffaele in Milan, Italy. (See BioWorld Today, Nov. 7, 2016.)